International Journal of Molecular Sciences (Jul 2022)
miR449 Protects Airway Regeneration by Controlling AURKA/HDAC6-Mediated Ciliary Disassembly
- Merit Wildung,
- Christian Herr,
- Dietmar Riedel,
- Cornelia Wiedwald,
- Alena Moiseenko,
- Fidel Ramírez,
- Hataitip Tasena,
- Maren Heimerl,
- Mihai Alevra,
- Naira Movsisyan,
- Maike Schuldt,
- Larisa Volceanov-Hahn,
- Sharen Provoost,
- Tabea Nöthe-Menchen,
- Diana Urrego,
- Bernard Freytag,
- Julia Wallmeier,
- Christoph Beisswenger,
- Robert Bals,
- Maarten van den Berge,
- Wim Timens,
- Pieter S. Hiemstra,
- Corry-Anke Brandsma,
- Tania Maes,
- Stefan Andreas,
- Irene H. Heijink,
- Luis A. Pardo,
- Muriel Lizé
Affiliations
- Merit Wildung
- Molecular & Experimental Pneumology Group, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, 37075 Gottingen, Germany
- Christian Herr
- Department of Internal Medicine V, Saarland University, 66421 Homburg, Germany
- Dietmar Riedel
- Laboratory for Electron Microscopy, Max Planck Institute for Multidisciplinary Sciences, 37075 Goettingen, Germany
- Cornelia Wiedwald
- Molecular & Experimental Pneumology Group, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, 37075 Gottingen, Germany
- Alena Moiseenko
- Immunology & Respiratory Department, Boehringer Ingelheim Pharma GmbH, 88400 Biberach an der Riss, Germany
- Fidel Ramírez
- Global Computational Biology and Digital Sciences Department, Boehringer Ingelheim Pharma GmbH, 88400 Biberach an der Riss, Germany
- Hataitip Tasena
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9712 Groningen, The Netherlands
- Maren Heimerl
- Molecular & Experimental Pneumology Group, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, 37075 Gottingen, Germany
- Mihai Alevra
- Institute of Neuro- and Sensory Physiology, Goettingen University, 37073 Goettingen, Germany
- Naira Movsisyan
- Oncophysiology Group, Max Planck Institute for Multidisciplinary Sciences, 37075 Goettingen, Germany
- Maike Schuldt
- Molecular Oncology, University Medical Center Goettingen, 37077 Goettingen, Germany
- Larisa Volceanov-Hahn
- Molecular & Experimental Pneumology Group, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, 37075 Gottingen, Germany
- Sharen Provoost
- Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
- Tabea Nöthe-Menchen
- Department of General Pediatrics, University Hospital Muenster, 48149 Muenster, Germany
- Diana Urrego
- Oncophysiology Group, Max Planck Institute for Multidisciplinary Sciences, 37075 Goettingen, Germany
- Bernard Freytag
- Molecular Oncology, University Medical Center Goettingen, 37077 Goettingen, Germany
- Julia Wallmeier
- Department of General Pediatrics, University Hospital Muenster, 48149 Muenster, Germany
- Christoph Beisswenger
- Department of Internal Medicine V, Saarland University, 66421 Homburg, Germany
- Robert Bals
- Department of Internal Medicine V, Saarland University, 66421 Homburg, Germany
- Maarten van den Berge
- Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9712 Groningen, The Netherlands
- Wim Timens
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9712 Groningen, The Netherlands
- Pieter S. Hiemstra
- Department of Pulmonology, Leiden University Medical Centre, 2333 Leiden, The Netherlands
- Corry-Anke Brandsma
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9712 Groningen, The Netherlands
- Tania Maes
- Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
- Stefan Andreas
- Molecular & Experimental Pneumology Group, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, 37075 Gottingen, Germany
- Irene H. Heijink
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9712 Groningen, The Netherlands
- Luis A. Pardo
- Oncophysiology Group, Max Planck Institute for Multidisciplinary Sciences, 37075 Goettingen, Germany
- Muriel Lizé
- Molecular & Experimental Pneumology Group, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, 37075 Gottingen, Germany
- DOI
- https://doi.org/10.3390/ijms23147749
- Journal volume & issue
-
Vol. 23,
no. 14
p. 7749
Abstract
Airway mucociliary regeneration and function are key players for airway defense and are impaired in chronic obstructive pulmonary disease (COPD). Using transcriptome analysis in COPD-derived bronchial biopsies, we observed a positive correlation between cilia-related genes and microRNA-449 (miR449). In vitro, miR449 was strongly increased during airway epithelial mucociliary differentiation. In vivo, miR449 was upregulated during recovery from chemical or infective insults. miR0449−/− mice (both alleles are deleted) showed impaired ciliated epithelial regeneration after naphthalene and Haemophilus influenzae exposure, accompanied by more intense inflammation and emphysematous manifestations of COPD. The latter occurred spontaneously in aged miR449−/− mice. We identified Aurora kinase A and its effector target HDAC6 as key mediators in miR449-regulated ciliary homeostasis and epithelial regeneration. Aurora kinase A is downregulated upon miR449 overexpression in vitro and upregulated in miR449−/− mouse lungs. Accordingly, imaging studies showed profoundly altered cilia length and morphology accompanied by reduced mucociliary clearance. Pharmacological inhibition of HDAC6 rescued cilia length and coverage in miR449−/− cells, consistent with its tubulin-deacetylating function. Altogether, our study establishes a link between miR449, ciliary dysfunction, and COPD pathogenesis.
Keywords
